jggf.1 - Fondazione Santa Lucia

JGGF.1 – CEREBELLAR MAGNETIC 

STIMULATION: A POTENTIAL NEW APPROACH 

TO TREAT PATIENTS WITH DYSTONIA 

Responsabile scientifico del progetto 

GIACOMO KOCH 

Fondazione Policlinico Tor Vergata – Fondazione Santa Lucia 

Jacques and Gloria Goss – Weiler Foundation – Finanziamento 2011

Sezione III: Attività per progetti 

ABSTRACT 

In this project we aim to investigate how the induction of long-term 

synaptic plasticity in the human cerebellum may reduce sustained involuntary 

muscle contractions in patients with dystonia. We will also evaluate how this 

procedure may modulate motor control in patients with dystonia in comparison 

with healthy subjects. 

The long-lasting modulation of the cerebellar function will be obtained 

using repetitive transcranial magnetic stimulation (rTMS). To induce cerebellar 

plasticity we will exploit theta burst stimulation (TBS) protocols, that are known 

to mediate crucial mechanisms of synaptic plasticity, such as long term 

potentation (LTP) and long term depression (LTD). To detect the changes 

occurring in the cerebellar-cortical anatomo-functional circuits following 

cerebellar TBS, we will adopt a multidisciplinary approach, using combined 

neurophysiological (TMS) and neuroimaging (functional magnetic resonancefMRI 

and MRI-tractography using diffusion tensor imaging-DTI) techniques. 

These measures will be performed before and after the application of cerebellar 

TBS, in order to characterize the impact of rTMS-induced cerebellar plasticity 

on motor control and motor learning in these patients. 

In another set of experiments, in order to evaluate the potential clinical 

effectiveness, rTMS will be applied in a randomized controlled trial (RCT) 

during two weeks to different groups of patients affected by primary dystonia. 

We will use clinical scores as the primary outcome, and neurophysiological and 

behavioral measures as secondary outcomes. Therefore we aim to verify the 

safety and efficacy of this non invasive procedure, and identify which underlying 

mechanisms are crucial in improving motor functions in dystonic patients. 

INTRODUCTION TO THE TOPIC 

Dystonia is a movement disorder characterized by excessive involuntary 

muscle contraction. So far, its pathophysiology remains not completely 

understood. Previous studies historically pointed to an impaired inhibition at 

multiple levels of the central nervous system as a key pathophysiological 

element [Hallett 1998], together with a distorted sensorimotor representation 

of affected body parts [Garraux et al. 2004] and altered functions of the basal 

ganglia [Eidelberg et al. 1998; Gernert et al. 2002]. 

Yet, recent evidences have demonstrated an important role of cerebellar 

circuits in the pathophysiology of dystonia [Jinnah, Hess 2006]. For instance, 

patients affected by primary dystonia have structural, metabolic and functional 

changes of cerebellar circuits and MRI investigations revealed that patients 

with writer’s cramp show a grey matter decrease in cerebellum [Delmaire et al. 

2007]. Indeed, changes in microstructural imaging and metabolic activity of 

cerebellar-thalamo-cortical pathway have been observed in primary torsion 

dystonia [Carbon, Eidelberg 2009] and in hereditary dystonia [Carbon et al. 

2010]. Using magnetic resonance diffusion tensor imaging (DTI) and probabilistic 

tractography to identify the specific circuit abnormalities that underlie 

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JGGF.1 – Cerebellar magnetic stimulation: a potential new approach to treat patients... 

clinical penetrance in carriers of genetic mutations for dystonia, Argyelan 

and coll. [2009] revealed that the integrity of cerebello-thalamo-cortical fiber 

tracts is reduced in both manifesting and clinically non manifesting dystonia 

mutation carriers. In these subjects, reductions in cerebello thalamic connectivity 

correlated with increased motor activation responses, consistent with loss of 

inhibition at the cortical level. 

In primary dystonia, neurophysiologic evidence of an altered olivocerebellar 

pathway was also demonstrated [Teo et al. 2009]. In secondary 

dystonia, the role of cerebellum in pathophysiology of dystonia has been also 

recognized: for example, cervical dystonia was observed to appearing one day 

after cerebellar infarction, assuming that the destruction of olivo-cerebellar 

pathway was the mechanism that caused dystonia [Zadro et al. 2008]. Taken 

together, these data strongly support the hypothesis of cerebellar involvement 

in the pathogenesis of dystonia. 

Nowadays, cerebellar function, in particular its influence on cerebral 

motor cortex, can be studied non-invasively using transcranial magnetic 

stimulation (TMS). 

rTMS is currently emerging as a promising therapeutic tool for treating 

refractory neuropsychiatric diseases on the basis of neural network modulations, 

and can be considered as a modern, non-invasive and non-painful alternative to 

electrical stimulation [Kobayashi, Pascual-Leone 2003]. The potential of rTMS 

as a tool to induce plastic changes in humans has been recently demonstrated 

through the development of the new TBS protocol, a novel form of rTMS that is 

capable of increasing or decreasing cortical excitability in healthy subjects for up 

to 60 min after the end of stimulation [Huang et al. 2005]. In analogy with the 

well-known protocols able to induce LTP or LTD in animal brain slices [Hess, 

Donoghue 1996], TBS makes use of brief trains of high frequencies of 

stimulation (up to 50 Hz) and employs very low intensity of stimulation to induce 

focal long-lasting changes in cortical excitability. Continuous TBS (cTBS) is able 

to decrease the excitability of the primary motor cortex, activating LTD-like 

mechanisms, while the opposite effect may be induced when the brief trains are 

intermittent (iTBS). Moreover, when applied repeatedly over several days, these 

protocols are able to induce persistent clinical changes [Ridding, Rothwell 1997]. 

The physiology of the cerebellar-thalamo-cortical pathway activated by 

magnetic stimulation has been recently clarified. It has been proposed that 

cerebellar TMS activates the Purkinje cells of the superior cerebellum; such 

activation results in an inhibition of the dentate nucleus, which is known to 

exert a background tonic facilitatory drive onto the contralateral motor cortex 

(M1) through synaptic relay in the ventral lateral thalamus [Middleton, Strick 

2000; Dum, Strick 2003]. This in turn leads to an inhibition of the contralateral 

M1, due to a reduction in dentato-thalamo-cortical facilitatory drive [Ugawa 

et al. 1994; 1997; Pinto, Chen 2001; Daskalakis et al. 2004; Reis et al. 2008]. 

Recently, considering previous animals studies showing the existence of both 

LTP- and LTD-like mechanisms in the cerebellum [Ito 2001; 2002; Kase et al. 

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1980; Maffei et al. 2002; 2003; D’Angelo et al. 1999], Koch and colleagues 

[2008] demonstrated that the TBS protocols are able to induce bi-directional 

and long-lasting changes in the excitability of the cerebello-thalamo-cortical 

circuits in humans also, and therefore to activate different mechanisms of 

synaptic plasticity when applied over the cerebellum. 

These results gave way to the possibility of modulating the excitability of 

cerebellar circuits in vivo, with clear implications to study the physiology of 

cerebellar plasticity and with possible translational approaches to treat several 

psychiatric and neurological disorders, as recently demonstrated in the case 

of Parkinson’s disease [Koch et al. 2009]. 

In particular, we found that another movement disorder that also involves 

dystonic postures, namely levodopa induced dyskinesia (LID) in Parkinson’s 

disease patients, was successfully improved by means of cerebellar TBS [Koch 

et al. 2009]. A two week course of cerebellar TBS was able to induce a 

persistent reduction of LID that lasted up to one month after the end of the 

treatment. This study demonstrates that cerebellar TBS has an antidyskinetic 

effect in Parkinson’s disease patients with LID, likely due to modulation of 

cerebello-thalamo-cortical pathways. 

Given that the integrity of cerebello-thalamo-cortical fiber tracts is reduced 

in dystonic patients and that the reduction in cerebellothalamic connectivity 

correlates with increased motor activation responses [i.e. Argyelan et al. 2009], 

we hypothesize that cerebellar TBS, by changing the excitability of these 

cerebello-thalamo-cortical pathways, may be able to improve the functioning of 

these altered circuits and thus lead to a significant clinical improvement. 

SPECIFIC GOALS OF THE PROJECT AND DETAILED RESEARCH PLAN 

1. As a the first pillar of the current project, cerebellar TBS will be applied 

to patients with dystonia, to evaluate the potential clinical effectiveness 

of the non-invasive induction of cerebellar long term synaptic plasticity 

on dystonic symptoms. 

In a previous work we found that another movement disorders that also 

involves dystonic postures, namely levodopa induced dyskinesia (LID) in 

Parkinson’s disease patients, was successfully improved by means of cerebellar 

cTBS [Koch et al. 2009]. Thus, in the current project we will study the effects 

of the cTBS protocol applied over the cerebellum of different groups of 

patients with dystonia. 

Hence, we will investigate the clinical potential of repeated sessions of 

cerebellar cTBS in patients with primary dystonia. 

Diagnosis of dystonia will be made by expert neurologists based on clinical 

and anamnestic data and on physical examination. In patients who receive 

botulinum toxin injections experiments will be carried out at least 4 months 

after their last injection. In all the other patients medications producing the 

best control of dystonic symptoms will be fixed for at least 1 month before and 

during the study. 

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The study has already been approved by the local ethical committee and 

all the subjects will give a written informed consent. 

Dystonic patients will undergo a two week period of bilateral cerebellar 

cTBS [Koch et al. 2009]. In each group, patients will be randomized to real 

(n=20) or sham (n=20) cerebellar cTBS. There will be ten days of stimulation 

(five days per week, Monday to Friday). Cerebellar TBS will be applied daily 

at the same time in the morning (9 a.m.) for each patient. Two trains of cTBS 

(80% AMT, 600 pulses, duration 40 s) will applied over the left and right lateral 

cerebellum with a pause of 2 minutes between the 2 trains. The order of 

stimulation will be pseudo randomized in each subject in every session. The 

same procedure will be used for sham stimulation, but the coil will be angled 

at 90°, with its edge only resting on the scalp and stimulation directed 

elsewhere. Stimulus intensity, expressed as a percentage of the maximum 

stimulator output, will be set at 40% AMT [Koch et al. 2009]. 

The evaluation of patients through clinical scales will be performed by 

blinded raters 2 weeks before the experimental procedure (t1), 1 hour before 

starting the first session of stimulation (t0), the Monday following the 2-weeks 

stimulation (t1) and again after 4 and 8 weeks after the end of the stimulation 

period (t2 and t3). During the whole time of experimentation the patient will 

receive standard therapy. In each visit patients will be videotaped and rated 

using the following scales: Fahn-Marsden scale, Global Dystonia Rating Scale, 

Unified Dystonia Rating Scale and Toronto Scale. 

The feasibility of the project is supported by the promising preliminary 

data, which demonstrate the validity of the techniques and justify the study 

rationale. 

In fact, in a small pilot study, five dystonic patients have already been 

recruited, in order to verify the safety of the cerebellar TBS procedure. All 

patients showed a significant clinical improvement and no main side effect 

was reported. 

2. As a second pillar of the current project, we will adopt a multidisciplinary 

approach, to study how the induction of cerebellar synaptic plasticity 

may modulate the efficacy of the interconnected cerebello-thalamo-cortical circuits 

in dystonic patients. 

Cerebellar long-term synaptic plasticity has been implicated in cerebellar 

learning and motor control, that is exerted trough the modulation of cerebellarcortical 

networks. The cerebellum is massively interconnected with the cerebral 

cortex. The classical view of these interconnections is that the cerebellum receives 

information from widespread cortical areas, including portions of the frontal, 

parietal, temporal, and occipital lobes [Glickstein et al. 1985; Schmahmann 1996]. 

Indeed, it is now clear that efferents from the cerebellar nuclei project to multiple 

subdivisions of the ventrolateral thalamus [Percheron et al. 1996], which, in turn, 

project to a myriad of cortical areas, including regions of frontal, prefrontal, and 

posterior parietal cortex [Jones 1985]. Thus, the outputs from the cerebellum 

influence more widespread regions of the cerebral cortex than previously 

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recognized. This change in perspective is important because it provides the 

anatomical substrate for the output of the cerebellum to influence nonmotor as 

well as motor areas of the cerebral cortex [Strick et al. 2009]. 

Therefore, to better understand how plastic modifications of cerebellar 

circuits contribute to physiological processes of sensori-motor transformation 

and motor control in dystonic patients, we will investigate the changes 

occurring in the functional connections of cortico-cortical circuits interconnected 

with the cerebellum, by means of combined TMS and MRI methods 

[Koch, Rothwell 2009]. 

Effects of cerebellar iTBS and cTBS on anatomo-functional connectivity –In 

these experiments we will verify the impact of cerebellar stimulation on 

functional connectivity of interrelated cortical networks. We will test how the 

functional connections of the cerebello-thalamo-cortical pathway and of the 

cortico-cortical connections linking the posterior parietal cortex (PPC) with 

the ipsilateral M1, are modified following cerebellar iTBS or cTBS. These 

functional connections will be measured with subjects at rest. 

In these paradigms, a conditioning stimulus (CS) is first used to activate 

putative pathways to M1 from the site of stimulation, while a second test 

stimulus (TS), delivered over M1 a few ms later probes any changes in 

excitability that may be produced by the input [Ugawa et al. 1995; Koch, 

Rothwell 2009]. These methods allow to measure causal interactions and real 

time changes in the connections [Koch, Rothwell 2009]. 

Therefore, by means of bifocal TMS we will investigate the following 

pathways: 

1) Cerebellar-thalamo-cortical pathway. Bifocal TMS will be applied to 

explore the connectivity between the cerebellar hemisphere and the contralateral 

motor cortex. We will apply this protocol in a sample of 20 dystonic patients and 

20 healthy age matched controls. Electromyographic (EMG) traces will be 

recorded from the first dorsal interosseous (FDI) muscles of the right hand 

using 9-mm diameter, Ag-AgCl surface cup electrodes. The active electrode will 

be placed over the muscle belly and the reference electrode over the 

metacarpophalangeal joint of the index finger. We will use a paired pulse 

stimulation technique with two high-power Magstim 200 machines. Magstim 

200 Mono Pulse magnetic stimulators will be connected to two separate figureof-eight 

coils (70 mm in diameter). The paired-TMS technique consists of a 

conditioning stimulus (CS) followed by a suprathreshold test stimulus (TS) at 

different ISIs. TS will be applied over the left motor cortex, in the optimal scalp 

position for induction of the largest MEPs in the right FDI muscle. We will 

determine the site of application of the CS by means of the neuronavigation 

system, using individual anatomical magnetic resonance images. The coil will 

be positioned over the superior posterior lobule of the right cerebellar 

hemisphere [Koch et al. 2007]. Mean peak-to-peak amplitude of the conditioned 

MEP at each ISI will then be expressed as the percentage of the mean peak-topeak 

amplitude of the unconditioned test MEP in that condition. 

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2) Parieto-motor functional connection. We will apply this protocol in a 

sample of 20 dystonic patients and 20 healthy age matched controls. 

The PPC is strongly interconnected with the premotor and motor cortices 

in the same hemisphere through distinct systems of fibers in the white matter 

that take origin mainly from the superior longitudinal fasciculus. These 

cortico-cortical connections are thought to transfer crucial information 

relevant for planning movements in space and to integrate visuo-motor 

transformations [Mountcastle et al. 1975; Mountcastle 1995; Kalaska et al. 

1990; Kalaska, Crammond 1995; Johnson et al. 1996; Caminiti et al. 1996; 

Andersen, Buneo 2002; Cohen, Andersen 2002]. We recently showed that it is 

possible to test these cortico-cortical connections in humans using a bifocal 

transcranial magnetic stimulation protocol [Koch et al. 2007a; 2008a; 2008b]. 

In this paradigm a CS TMS pulse is applied over the PPC, shortly prior to a test 

pulse over the hand area of motor cortex (M1). The latter pulse evokes a small 

twitch in contralateral hand muscles that can be measured with surface EMG. 

When the interval between the PPC pulse and the M1 pulse is around 4-6 ms, 

the EMG response triggered by the M1 pulse is enhanced, indicating that the 

PPC pulse altered excitability of M1, and thus implying functional PPC-M1 

connectivity. The site of the conditioning PPC pulse that leads to the most 

pronounced impact on M1 lays over the caudal part of the intraparietal sulcus 

(cIPS), presumably activating a pathway that involves the superior longitudinal 

fasciculus (SFL) [Koch et al. 2010]. 

Cerebellar theta burst stimulation (TBS) – We will use a MagStim Super Rapid 

magnetic stimulator, connected to a figure-of-eight coil (diameter of 90 mm) to 

deliver the bursts of stimuli of TBS: bursts repeat at 5 Hz (i.e. every 200 ms), while 

each burst consists of three stimuli repeating at 50 Hz. For iTBS, a 2 s train of TBS 

at 80% active motor threshold (AMT) is repeated 20 times, every 10 s for a total 

of 190 s (600 pulses); in the cTBS a 40 s train of uninterrupted TBS is given (600 

pulses) [Huang et al. 2005]. TMS will be applied over the lateral cerebellum using 

the same scalp co-ordinates as those adopted in previous studies, in which MRI 

reconstruction and neuronavigation systems showed that cerebellar TMS over 

this site predominantly targets the posterior and superior lobules of the lateral 

cerebellum [Koch et al. 2008]. 

The effects of cTBS and iTBS will be investigated in two different sessions 

for each subject, performed at least one week apart. The cerebellar-thalamocortical 

pathway and the parieto-motor functional connection will be examined 

either before and immediately after a single session of iTBS or cTBS. 

Anatomical reconstruction of functional connections – To obtain detailed 

anatomical information on the white matter pathways that mediate the 

neurophysiological and behavioral interactions, we will use DT-MRI in all 

subjects. DT-MRI can allow in vivo reconstruction of white matter fiber 

bundles, based on the assumption that the principal direction of tissue water 

diffusion is parallel to the main fiber direction in every voxel [Basser, Pierpaoli 

2002]. The orientation dependence of diffusion can then be quantified by 

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fractional anisotropy (FA) at each voxel [Johansen-Berg, Bherens 2006]. Since 

FA has been shown to reflect functionally relevant microstructural properties 

of white matter [Boorman et al. 2007; Koch et al. 2010], we will employ tractbased 

spatial statistics (TBSS) [Smith et al. 2006] to analyze local correlations 

between individual estimates of FA and the neurophysiological changes 

obtained after cerebellar iTBS or cTBS. 

We will also collect measures of resting-state fMRI imaging to define 

subregions within the cerebellar cortex based on their functional connectivity 

with the cerebral cortex. We will map resting-state functional connectivity 

voxel-wise across the cerebellar cortex, for cerebral-cortical masks covering 

prefrontal, motor, somatosensory, posterior parietal, visual, and auditory 

cortices [Della Maggiore et al. 2010]. 

TIMELINES AND DELIVERABLES 

The project will be performed at the IRCCS Santa Lucia in Rome, Italy 

and at the University Hospital Virgen del Rocío, in Seville, Spain 

– The TMS lab led by Giacomo Koch at the IRCCS Santa Lucia in Rome 

will investigate the clinical efficacy of cerebellar magnetic stimulation and 

how motor corticocerebellar circuits change in dystonic patients following 

rTMS. In our lab we are already furnished with rTMS equipment (Magstim 

Super Rapid), two single-pulse TMS machines, and recording systems for 

acquisition of EMG signals (i.e. the CED Power1401 data acquisition interface 

and the Digitimer LTD 8-Channel Patient Amplifier System-D360), all that will 

be available for the current project. The team involved in these experiments 

will include neurologists, neurophysiologists and neuropsychologists, experts 

in the fields of cortical stimulation. 

– The Neuroimaging lab of the IRCCS Santa Lucia in Rome led by 

Marco Bozzali will collaborate in this project. fMRI and DTI tractography 

investigations will be performed in healthy subjects and in dystonic patients, 

to further characterize the anatomo-functional changes induced by rTMS. 

– Pablo Mir, Director of the Movement disorder unit of the University 

Hospital Virgen del Rocío, in Seville (Spain) will be a key co applicant of the 

project. His team will be involved in TMS investigations on the activity of 

corticocerebellar circuits in dystonic patients and will actively contributed in 

the clinical investigations of the rTMS efficacy. Mir’s lab is also furnished with 

the same rTMS equipment (Magstim Super Rapid) and recording systems for 

acquisition of EMG signals (i.e. the CED Power1401 data acquisition interface 

and the Digitimer LTD 8-Channel Patient Amplifier System-D360), all that will 

be available for the current project. 

The project will extend over 2 years. The plan will be the following: 

Months 0-12: Analysis of neurophysiological effects of cerebellar TBS in 

voluntary healthy subjects and dystonic patients – Bifocal TMS and paired 

pulse TMS experiments will be performed in the same subjects and in selected 

groups of patients affected by dystonia (n=20). Specific scheduling will depend 

682 2011


on patient availability. Continuous transfer of information between clinical and 

physiological research groups will allow to improve parameters in the 

stimulation protocols. In order to obtain anatomo-functional complementary 

information, a subset of the voluntary healthy subjects and patients tested in 

the TMS unit will also perform MRI scanning. Anatomical information 

concerning the cerebellar-cortical connections involved in the behavioral and 

neurophysiological changes induced by cerebellar TBS will be detected using 

DTI MRI. Further information on the related patterns of functional connections 

will also be provided by resting state fMRI. 

Months 6-18: Patients will be screened and recruited for the clinical study on 

the cerebellar stimulation efficacy – We will recruit 40 patients with primary 

dystonia among the two movements disorders centers in Rome and Seville. After 

a deep clinical examination, patients will be randomly assigned either to a real 

TBS group or to a placebo group. The evaluation of patients through clinical 

scales will be performed by blinded raters 2 weeks before the experimental 

procedure (t1), 1 hour before starting the first session of stimulation (t0), the 

Monday following the 2-weeks stimulation (t1) and again after 4 and 8 weeks 

after the end of the stimulation period (t2 and t3). During the whole time of 

experimentation the patient will receive standard therapy. In each visit patients 

will be videotaped and rated using the following scales: Fahn-Marsden scale, 

Global Dystonia Rating Scale , Unified Dystonia Rating Scale and Toronto Scale. 

Months 18-24: The clinical data will be analyzed and time will be dedicated 

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